Design and evaluation of "pathogen-mimicking" polyanhydride delivery platforms for drug and vaccine applications

Abstract

<p>Vaccines and antibiotics have had a profound impact on human and animal health in the last century. Despite their success, there are several disadvantages associated with current regimens, including multiple immunizations that result in poor patient compliance, high reactogenicity, unpleasant side effects, and poor efficacy against intracellular pathogens. In this regard, innovative delivery platforms can facilitate the development of effective single-dose treatment regimens to control emerging and re-emerging infectious diseases. The work presented in this dissertation describes how rational design principles can be successfully employed to develop targeted polyanhydride platforms for drug and vaccine delivery. Initial studies sought to define the interactions of various polyanhydride micro- and nanoparticle formulations with antigen presenting cells (APCs), a type of immune cell critical to the initiation of immune responses. Experiments focused on particle internalization, uptake mechanism(s), and intracellular trafficking revealed striking chemistry and size dependent effects. Knowledge gained from these studies was then used to strategically select specific particle sizes and chemistries to test the efficacy of doxycycline-loaded particles against an in vitro infection with the intracellular pathogen <em>Brucella</em>.</p> <p>Subsequent chapters in this dissertation detail how a multidisciplinary approach utilizing tools from cell biology, immunology, biomaterials engineering, carbohydrate chemistry, and informatics analysis delineated the complex patterns observed during host-pathogen interactions. These observations were then used to identify the properties of polyanhydride nanoparticles that mimicked the ability of bacterial pathogens to induce a robust immune response. Specifically, surface functionalization, including the addition of carbohydrates, made nanoparticles more "pathogen-mimicking" in terms of their intracellular fate, persistence and APC activation compared to <em>Yersinia pestis</em> or <em>Escherichia coli</em>. Carbohydrate functionalization also enhanced microparticle internalization by targeting the C-type lectin receptors present on APCs. Studies were also performed to evaluate the effect of vaccine antigen functionalization in combination with the polyanhydride nanoparticle platform. Modification of the plague antigen F1-V with α-galactose induced T cell expansion as well as a high titer, high avidity antibody response with broad epitope recognition of F1-V peptides when administered with polyanhydride nanoparticles. In summary, the studies described herein support the rational design and selection of delivery platforms to meet the needs of a spectrum of biomedical applications, including drug and vaccine delivery.</p>